To date, irreversible cysteine protease inhibitors have been used only as biochemical tools for the characterization of proteases. Prototek is developing safe, effective oral protease inhibitors for a variety of therapeutic applications, including the treatment of P. carinii pneumonia, arthritis, cancer and the rejection of transplanted organs. One or more of Prototek's inhibitors may have utility in the treatment of malaria and Chagas' disease. The proposed research would allow the Company to extend tits work on cysteine protease inhibitors to optimize their specificity toward the cathepsin-like proteases of P. falciparum and T. cruzi. A plan is presented to optimize the structures of the peptide and non- peptide portions of the inhibitors to specific parasite proteases. The synthesis of 18 peptide fragments and up to 10 non-peptide portions is planned. The in vitro and in vivo efficacy of the inhibitors will be tested in appropriate models during this Phase I SBIR grant. PROPOSED COMMERCIAL APPLICATION: This proposal is focused on the development of safe and effective therapeutic treatments for malaria or Chagas' disease. If successful, the therapeutics will be submitted to clinical trials in connection with the Wold Health Organization, the Department of Defense or a pharmaceutical company.